Early relapse within 18 months is a powerful dynamic predictor for prognosis and could revise static risk distribution in multiple myeloma.

BACKGROUND: The duration of response to treatment is a major prognostic factor, and early relapse (ER) strongly predicts inferior survival in multiple myeloma (MM). However, the definitions of ER in MM vary from study to study and how to dynamically integrate risk distribution is still unsolved. METHODS: This study evaluated these ER definitions and further investigated the underlying relationship with static risk distribution in 629 newly diagnosed MM (NDMM) patients from the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). RESULTS: These data indicated that early relapse within 18 months (ER18) after initial treatment was the best time point for identifying early progression and dynamic high-risk in MM. The ER18 population (114 of 587, 19.4%) presented with more aggressive biologic features and the inferior response to treatment compared to a reference cohort (p < .001), with a significantly short median overall survival (OS) of 28.9 months. Multivariate analyses confirmed the most significant prognostic value of ER18 on OS in the context of International Staging System stage, elevated lactate dehydrogenase, thrombocytopenia, cytogenetic abnormalities, and treatment (hazard ratio, 4.467; p < .001). The authors also described the specific transitions from static risk profile to dynamic risk distribution and then constructed a mixed-risk-pattern to identify four novel populations with distinct survival (p < .001). Additionally, the authors proposed a second-state model that predicts dynamic risk changes, enabling a complementary role to the Revised International Staging System model in facilitating individualized systematic treatment. CONCLUSIONS: Collectively, this study concludes that ER18 is a simple and dynamic prognostic predictor in MM. In addition to static risk assessment, dynamic risk plays an important role in survival prediction.

Minor clone of del(17p) provides a reservoir for relapse in multiple myeloma.

The deletion of chromosome 17p (del(17p)) is considered a crucial prognostic factor at the time of diagnosis in patients with multiple myeloma (MM). However, the impact of del(17p) on survival at different clonal sizes at relapse, as well as the patterns of clonal evolution between diagnosis and relapse and their prognostic value, has not been well described. To address these issues, we analyzed the interphase fluorescence in situ hybridization (iFISH) results of 995 newly diagnosed MM (NDMM) patients and 293 patients with MM at their first relapse. Among these patients, 197 had paired iFISH data at diagnosis and first relapse. Our analysis of paired iFISH revealed that a minor clone of del(17p) at relapse but not at diagnosis was associated with poor prognosis in MM (hazard ratio for median overall survival 1.64 vs. 1.44). Fifty-six and 12 patients developed one or more new cytogenetic abnormalities at relapse, mainly del(17p) and gain/amp(1q), respectively. We classified the patients into six groups based on the change patterns in the clonal size of del(17p) between the two time points. Patients who did not have del(17p) during follow-up showed the best outcomes, whereas those who acquired del(17p) during their disease course, experienced compromised survival (median overall survival: 61.3 vs. 49.4 months; hazard ratio =1.64; 95% confidence interval: 1.06-2.56; P<0.05). In conclusion, our data confirmed the adverse impact of a minor clone of del(17p) at relapse and highlighted the importance of designing optimal therapeutic strategies to eliminate high-risk cytogenetic abnormalities (clinicaltrials gov. identifier: NCT04645199).

Immunophenotypic profile defines cytogenetic stability and unveils distinct prognoses in patients with newly-diagnosed multiple myeloma (NDMM).

Prognostic significance of multiple immune antigens in multiple myeloma has been well established. However, a level of uncertainty remains regarding the intrinsic relationship between immunophenotypes and cytogenetic stability and precise risk stratification. To address these unresolved issues, we conducted a study involving 1389 patients enrolled in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Our results revealed that the correlation between antigen expression and cytogenetics is more prominent than cytopenia or organ dysfunction. Most immune antigens, apart from CD38, CD138, and CD81, exhibit significant associations with the incidence of at least one cytogenetic abnormality. In turn, we identified CD138-low/CD27-neg as specific adverse immunophenotypic profile, which remaining independent impact on progression-free survival (HR, 1.49; P = 0.007) and overall survival (HR, 1.77; P < 0.001) even in the context of cytogenetics. Importantly, CD138-low/CD27-neg profile was also associated with inferior survival after first relapse (P < 0.001). Moreover, the antigen expression profiles were not strictly similar when comparing diagnosis and relapse; in particular, the CD138-low/CD27-neg pattern was notably increased after disease progression (19.1 to 29.1%; P = 0.005). Overall, our study demonstrates that diverse immune profiles are strongly associated with cytogenetic stability, and a specific immunophenotype (CD138-low/CD27-neg) could effectively predict prognoses across different disease stages.

Development and validation of an individualized and weighted Myeloma Prognostic Score System (MPSS) in patients with newly diagnosed multiple myeloma.

Current standard predictive models of disease risk do not adequately account for the heterogeneity of survival outcomes in patients with new-diagnosed multiple myeloma (NDMM). In this retrospective, multicohort study, we collected clinical and genetic data from 1792 NDMM patients and identified the prognostic impact of all features. Using the top-ranked predictive features, a weighted Myeloma Prognostic Score System (MPSS) risk model was formulated and validated to predict overall survival (OS). In the training cohort, elevated lactate dehydrogenase level (LDH), International Staging System (ISS) Stage III, thrombocytopenia, and cumulative high-risk cytogenetic aberration (HRA) numbers were found to have independent prognostic significance. Each risk factor was defined as its weighted value respectively according to their hazard ratio for OS (thrombocytopenia 2, elevated LDH 1, ISS III 2, one HRA 1, and ≥2 HRA 2, points). Patients were further stratified into four risk groups: MPSS I (22.5%, 0 points), II (17.6%, 1 points), III (38.6%, 2-3 points), and IV (21.3%, 4-7 points). MPSS risk stratification showed optimal discrimination, as well as calibration, of four risk groups with median OS of 91.0, 69.8, 45.0, and 28.0 months, for patients in MPSS I to IV groups (p < .001), respectively. Importantly, the MPSS model retained its prognostic value in the internal validation cohort and an independent external validation cohort, and exhibited significant risk distribution compared with conventional prognostic models (R-ISS, R2-ISS, and MASS). Utilization of the MPSS model in clinical practice could improve risk estimation in NDMM patients, thus prompting individualized treatment strategies.

Diagnostic efficiency of [68 Ga]Ga-DOTA-FAPI-04 in differentiating periprosthetic hip joint infection and aseptic failure.

PURPOSE: To assess the efficiency of [68 Ga]Ga-DOTA-FAPI-04 in diagnosing periprosthetic hip joint infection and establish a diagnostic standard of clinical significance based on uptake pattern. METHODS: [68 Ga]Ga-DOTA-FAPI-04 PET/CT was performed in patients with symptomatic hip arthroplasty from December 2019 to July 2022. The reference standard was based on the 2018 Evidence-Based and Validation Criteria. Two diagnostic criteria, SUVmax and uptake pattern, were used to diagnose PJI. Meanwhile, original data were imported into IKT-snap to draw the view of interest, A.K. was used to extract features of clinical cases, and unsupervised clustering analysis was applied according to the groups. RESULTS: A total of 103 patients were included, 28 of whom had PJI. The area under the curve of SUVmax was 0.898, which was better than that of all of the serological tests. The cutoff value of SUVmax was 7.53, and the sensitivity and specificity were 100 and 72%, respectively. The sensitivity, specificity and accuracy of the uptake pattern were 100, 93.1 and 95%, respectively. In radiomics analysis, the features of PJI were significantly different from those of aseptic failure. CONCLUSION: The efficiency of [68 Ga]Ga-DOTA-FAPI-04 PET/CT in diagnosing PJI showed promising results, and the diagnostic criteria of the uptake pattern were more clinically instructive. Radiomics also showed certain application prospects in the field of PJI. TRIAL REGISTRATION NUMBER: Trial registration: ChiCTR2000041204. Registered 24 September 2019.

Impact of residual tumor cells in the stem cell collection on multiple myeloma patients receiving autologous stem cell transplantation.

Autologous stem cell transplantation (ASCT) is the standard therapy for patients with transplant-eligible multiple myeloma (TEMM). However, the ideal depth of response required before ASCT and the impact of residual tumor cells in the stem cell collection (SCC) on survival remains unclear. Here we collected data of 89 patients with TEMM undergoing ASCT and analyzed the minimal residual disease of SCC (cMRD) and bone marrow (BM) (mMRD) before transplantation. Before ASCT, 31.5% and 76.4% of patients achieved MRD negativity in BM and SCC, respectively. Tumor cells were less in SCC samples than that in BM samples. Neoplastic cells in SCC could be observed in patients with different responses after induction therapy, and there were no significant differences in the percentage and level of cMRD among these subgroups (P > 0.05). No correlation was found between the cMRD status and the response patients achieved after ASCT (P > 0.05). The median follow-up was 26.8 months. mMRD negativity before ASCT was associated with longer PFS (55.9 vs. 27.1 months; P = 0.009) but not OS (not reached vs. 58.9 months; P = 0.115). Patients with different cMRD statuses before ASCT experienced similar PFS (40.5 vs. 76.4 months for negativity vs. positivity; P = 0.685) and OS (not reached vs. 58.8 months for negativity vs. positivity; P = 0.889). These results suggested that detectable cMRD does not significantly predict the inferior post-ASCT response or shorter survival, and patients are eligible to undergo ASCT upon achieving partial response.

Comparison between primary repair and augmented repair with gastrocnemius turn-down flap for acute Achilles tendon rupture: a retrospective study with minimum 2-year follow-up.

BACKGROUND: To explore and compare the clinical outcomes in patients undergoing primary repair versus augmented repair with a gastrocnemius turn-down flap for acute Achilles tendon rupture. METHODS: From 2012 to 2018, the clinical data of 113 patients with acute Achilles tendon rupture who were treated with primary repair or augmented repair with a gastrocnemius turn-down flap by the same surgeon were retrospectively reviewed. The patients' preoperative and postoperative scores on the visual analog scale (VAS), American Orthopaedic Foot and Ankle Society Ankle⁃Hindfoot (AOFAS) score, the Victorian Institute of Sport Assessment⁃Achilles (VISA-A), the Achilles tendon total rupture score (ATRS), and the Tegner Activity Scale were examined and compared. The postoperative calf circumference was measured. A Biodex isokinetic dynamometer was used to evaluate the plantarflexion strength on both sides. The time to return to life and exercise as well as the strength deficits in both groups were recorded. Finally, the correlation analyses between patient characteristics and treatment details with clinical outcomes were conducted. RESULTS: In total, 68 patients were included and completed the follow-up. The 42 and 26 patients who were treated with primary repair and augmented repair were assigned to group A and B, respectively. No serious postoperative complications were reported. No significant between-group differences in any outcomes were observed. It was found that female sex was correlated with poorer VISA-A score (P = 0.009), complete seal of paratenon was correlated with higher AOFAS score (P = 0.031), and short leg cast was correlated with higher ATRS score (P = 0.006). CONCLUSIONS: Augmented repair with a gastrocnemius turn-down flap provided no advantage over primary repair for the treatment of acute Achilles tendon rupture. After surgical treatment, females tended to had poorer outcomes, while complete seal of paratenon and short leg cast contributed to better results. LEVEL OF EVIDENCE: Cohort study; Level of evidence, 3.

Efficacy of Platelet-Rich Plasma Versus Placebo in the Treatment of Tendinopathy: A Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To evaluate the efficacy of platelet-rich plasma (PRP) injections versus placebo in the treatment of tendinopathy. DATA SOURCES: We performed a systematic literature search in MEDLINE, Embase, Scopus, CINAHL, Cochrane Library, and ClinicalTrials.gov through November 2020 to identify randomized controlled trials (RCTs) that evaluated the clinical efficacy of PRP versus placebo for the treatment of tendinopathy. Outcomes were analyzed on an intention-to-treat basis with random-effects models. MAIN RESULTS: A total of 13 RCTs were included in this meta-analysis. The pooled analysis showed no significant difference in pain relief at 4 to 6 weeks (standard mean difference [SMD]: -0.18, 95% confidence intervals [CI]: -0.62 to 0.26), 12 weeks (SMD: -0.14, 95% CI: -0.55 to 0.26), and ≥24 weeks (SMD: -0.56, 95% CI: -1.16 to 0.05) or function improvement at 4 to 6 weeks (SMD: 0.11, 95% CI: -0.13 to 0.35), 12 weeks (SMD: 0.18, 95% CI: -0.13 to 0.49), and ≥24 weeks (SMD: 0.26, 95% CI: -0.14 to 0.66) for PRP compared with placebo in the treatment of tendinopathy. The sensitivity analysis indicated no significant difference in pain relief or function improvement at 12 weeks between PRP and placebo for different types of tendinopathies, treatment regimens, leukocyte concentrations, or cointerventions. CONCLUSIONS: Platelet-rich plasma injection was not found to be superior to placebo in the treatment of tendinopathy, as measured by pain relief and functional improvement at 4 to 6, 12, and ≥24 weeks.

Arthroscopic subacromial decompression improves long-term functional outcome in patients with subacromial impingement: A systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The effect of arthroscopic subacromial decompression for impingement syndrome is still under debate. The purpose of this study was to evaluate short-term and long-term effects of arthroscopic decompression in patients with subacromial impingement. METHODS: A systematic literature search was performed in Pubmed, Embase, Scopus, Cochrane Library, and ClinicalTrials.gov through March 2021 to identify randomized controlled trials (RCTs) that evaluated the clinical effects of arthroscopic decompression versus placebo surgery or exercise therapy for patients with subacromial impingement. Outcomes were analyzed on an intention-to-treat basis with random-effects models. RESULTS: Nine RCTs were included in the meta-analysis. The pooled analysis showed that arthroscopic decompression was associated with significantly better function improvement at 24-36 months and ≥ 60 months (24-36 months: SMD: 0.29, 95% CI: 0.10 to 0.48, P = 0.002; ≥ 60 months: SMD, 0.65, 95% CI, 0.20 to 1.09, P=0.004) compared with control group. Moreover, the effect size of function improvement ≥ 60 months exceeded the minimum clinically important difference (MCID). Additionally, sensitivity analysis indicated that compared with either exercise therapy or placebo surgery, arthroscopic decompression was associated with significantly better function improvement ≥ 60 months follow-up. However, there was no significant difference regarding pain relief at 6 months, 12 months, 24-36 months, ≥ 60 months, and function improvement at 6 months, 12 months for arthroscopic decompression compared with control group. CONCLUSION: After ≥ 60 months of follow-up, arthroscopic decompression in patients with subacromial impingement appears to render better function results than exercise therapy and placebo surgery. LEVEL OF EVIDENCE: I, systematic review and meta-analysis of level I studies.

Effectiveness of Curcuma longa extract versus placebo for the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.

The aim of this systematic review was to evaluate the efficacy and safety of all types of Curcuma longa extract versus placebo for knee osteoarthritis (OA) treatment. The research was conducted by using the databases of PubMed, Embase, Scopus, and Cochrane Library through April 2021. Randomized controlled trials (RCTs) that compared the effect of Curcuma longa extract with placebo for patients with knee OA were considered eligible. The pooled results were expressed as mean differences or relative risks with 95% confidence intervals. A total of 10 RCTs with 783 patients were eligible for this meta-analysis. The pooled analysis showed that Curcuma longa extract was associated with significantly better pain relief and functional improvement compared with placebo for knee OA. Moreover, the smallest effect sizes of VAS for pain and WOMAC total score exceeded the minimum clinically important differences (MCIDs). Current evidence indicates that, compared with placebo, Curcuma longa extract has more benefit in pain relief and functional improvement for symptomatic knee OA. However, considering the potential heterogeneity in the included studies, more future high-quality RCTs with large sample sizes are necessary to confirm the benefits of Curcuma longa extract on knee OA.

Assessment of Human Visual Acuity Using Visual Evoked Potential: A Review.

Visual evoked potential (VEP) has been used as an alternative method to assess visual acuity objectively, especially in non-verbal infants and adults with low intellectual abilities or malingering. By sweeping the spatial frequency of visual stimuli and recording the corresponding VEP, VEP acuity can be defined by analyzing electroencephalography (EEG) signals. This paper presents a review on the VEP-based visual acuity assessment technique, including a brief overview of the technique, the effects of the parameters of visual stimuli, and signal acquisition and analysis of the VEP acuity test, and a summary of the current clinical applications of the technique. Finally, we discuss the current problems in this research domain and potential future work, which may enable this technique to be used more widely and quickly, deepening the VEP and even electrophysiology research on the detection and diagnosis of visual function.

A genome-wide association study identifies new genes associated with developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is one of the most common congenital malformations and covers a spectrum of hip disorders from mild dysplasia to irreducible dislocation. The pathological mechanisms of DDH are poorly understood, which hampers the development of diagnostic tools and treatments. To gain insight into its disease mechanism, we explored the potential biological processes that underlie DDH by integrating pathway analysis tools and performing a genome-wide association study (GWAS). A total of 406 DDH-associated genes (P < 0.001) were identified by our GWAS using a Chinese Han cohort consisting of 386 DDH cases and 500 healthy controls (Set A). We verified the significant loci (P < 10-5 ) in another Chinese Han cohort consisting of 574 DDH patients and 569 healthy controls (Set B). An intronic Single Nucleotide Polymorphism (SNP) (rs61930502) showed significant association in Set A and Set B (P = 2.65 × 10-7 and 2.0 × 10-4 , respectively). The minor allele, rs61930502-A, which tended to prevent DDH showed a dominant effect. Heat shock 70 kDa protein 8 (HSPA8) showed the most direct interactions with other proteins which were coded by DDH-associated genes in the protein-protein interaction analysis. Interestingly, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis suggested a relation between DDH and the genes involved in type II diabetes mellitus pathway (P = 0.0067). Our genetic and protein interaction evidence could open avenues for future studies of DDH.

Inhibitory Effects of the Extracts of Juglans sigillata Green Husks on the Proliferation, Migration and Survival of KYSE150 and EC9706 Human Esophageal Cancer Cell Lines.

This study evaluated the antitumor activity of the extracts of green husks of Juglans sigillata Dode on esophageal cancer. KYSE150 EC9706 cells were treated with different concentrations of six components of the extracts of J. sigillata green husks. Cell viability was measured by MTT. Cell migration and cell invasion were measured by wound-healing assays and transwell assays, respectively. Cell apoptosis and cycle were measured by flow cytometry. The expression of cell migration, cell cycle and cell apoptosis regulatory proteins was analyzed by Western blotting. Only the three constituents, including EtOH extractives, EtOAc soluble fraction and gallic acid (GA), exhibited inhibitory effects on the cell viability, migration and invasion by decreasing MMP2 and MMP9 expression (all P < 0.05). Flow cytometry revealed that these three constituents also induced cell apoptosis by increasing Bax and cleaved caspase-3 but decreasing Bcl-2 in KYSE150 and EC9706 cells. Furthermore, these constituents arrested the cell cycle at G0/G1 by downregulating the expression of Cyclin D1 but upregulating p53 and phospho-p53 expression in KYSE150 cells. In conclusion, the green husks of J. sigillata may act as a potential inhibitor on esophageal cancer growth. GA was the major single active constituent of the extracts.

Neuroprotection by new ligustrazine-cinnamon acid derivatives on CoCl2-induced apoptosis in differentiated PC12 cells.

A new series of ligustrazine-cinnamon acid derivatives had been designed and synthesized as potential neuro-protective agents. Among the derivatives, 3a exhibited the promising neuroprotective activity (EC50 = 3.68 µM). Moreover, with the deep research of the drug pathway, it (the further mechanism researches) suggested compound 3a could inhibit the apoptosis of injured PC12 cells via blocking the mitochondria apoptosis pathway including up-regulation the ratio of Bcl-2/Bax, down-regulation the expression of cytochrome-c (Cyt-c) and inhibition of the activity of caspase-9 and -3. In addition, the structure-activity relationships (SARs) of novel compounds were also discussed.

The Role of Visual Noise in Influencing Mental Load and Fatigue in a Steady-State Motion Visual Evoked Potential-Based Brain-Computer Interface.

As a spatial selective attention-based brain-computer interface (BCI) paradigm, steady-state visual evoked potential (SSVEP) BCI has the advantages of high information transfer rate, high tolerance to artifacts, and robust performance across users. However, its benefits come at the cost of mental load and fatigue occurring in the concentration on the visual stimuli. Noise, as a ubiquitous random perturbation with the power of randomness, may be exploited by the human visual system to enhance higher-level brain functions. In this study, a novel steady-state motion visual evoked potential (SSMVEP, i.e., one kind of SSVEP)-based BCI paradigm with spatiotemporal visual noise was used to investigate the influence of noise on the compensation of mental load and fatigue deterioration during prolonged attention tasks. Changes in α, θ, θ + α powers, θ/α ratio, and electroencephalography (EEG) properties of amplitude, signal-to-noise ratio (SNR), and online accuracy, were used to evaluate mental load and fatigue. We showed that presenting a moderate visual noise to participants could reliably alleviate the mental load and fatigue during online operation of visual BCI that places demands on the attentional processes. This demonstrated that noise could provide a superior solution to the implementation of visual attention controlling-based BCI applications.

A New Oleanolic Acid Derivative against CCl4-Induced Hepatic Fibrosis in Rats.

A novel hepatoprotective oleanolic acid derivative, 3-oxours-oleana-9(11), 12-dien-28-oic acid (Oxy-Di-OA), has been reported. In previous studies, we found that Oxy-Di-OA presented the anti-HBV (Hepatitis B Virus) activity (IC50 = 3.13 µg/mL). Remarkably, it is superior to lamivudine in the inhibition of the rebound of the viral replication rate. Furthermore, Oxy-Di-OA showed good performance of anti-HBV activity in vivo. Some studies showed that liver fibrosis may affiliate with HBV gene mutations. In addition, the anti-hepatic fibrosis activity of Oxy-Di-OA has not been studied. Therefore, we evaluated the protective effect of Oxy-Di-OA against carbon tetrachloride (CCl4)-induced liver injury in rats. Daily intraperitoneally administration of Oxy-Di-OA prevented the development of CCl4-induced liver fibrosis, which was evidenced by histological study and immunohistochemical analysis. The entire experimental protocol lasted nine weeks. Oxy-Di-OA significantly suppressed the increases of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (p < 0.05). Furthermore, Oxy-Di-OA could prevent expression of transforming growth factor ß1 (TGF-ß1). It is worth noting that the high-dose group Oxy-Di-OA is superior to bifendate in elevating hepatic function. Compared to the model group, Oxy-Di-OA in the high-dose group and low-dose group can significantly reduce the liver and spleen indices (p < 0.05). The acute toxicity test showed that LD50 and a 95% confidence interval (CIs) value of Oxy-Di-OA were 714.83 mg/kg and 639.73-798.73 mg/kg via intraperitoneal injection in mice, respectively. The LD50 value of Oxy-Di-OA exceeded 2000 mg/kg via gavage in mice. In addition, a simple and rapid high performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated to study the pharmacokinetic characteristics of the compound. After single-dose oral administration, time to reach peak concentration of Oxy-Di-OA (Cmax = 8.18 ± 0.66 µg/mL) was 10 ± 2.19 h; the elimination half-life and area under the concentration-time curve from t = 0 to the last time of Oxy-Di-OA was 2.19 h and 90.21 µg·h/mL, respectively.

A Series of Oleanolic Acid Derivatives as Anti-Hepatitis B Virus Agents: Design, Synthesis, and in Vitro and in Vivo Biological Evaluation.

A series of oleanolic acid derivatives were synthesized by diverse reactions, including the introduction of conjugated alkadiene and epoxy ring moieties formed by means of photosensitized oxidation. Eosin Y was used as photosensitizer during this process. Next the cytotoxicity of the products was evaluated on HepG2.2.15 cells to determine the appropriate treatment concentration for the subsequent experiments. Most of the OA derivatives exhibited anti-HBV antigens secretion activity in HepG2.2.15 cells. Among the tested compounds, OA-4 (3.13 µg/mL) showed significant activity against the secretion of HBsAg, HBeAg, and HBV DNA replication with inhibitory ratios of 90.52% ± 1.78%, 31.55% ± 3.65%, and 94.57% ± 3.11% after 6 days, respectively. Besides, OA-4 was further investigated in a duck model with DHBV infection. When OA-4 was administered at a dosage of 500 mg/kg, the results revealed a significant inhibitory effects of DHBV at 19.94% ± 2.87%, 28.80% ± 3.62% and 29.25% ± 2.65% at days 5, 10, and 3 after the cessation of OA-4 treatment, respectively. It's worth noting that OA-4 is superior to lamivudine in the inhibition of rebound of viral replication rate. The structure-activity relationships of OA derivatives had been preliminary discussed, which should be useful to explore further novel anti-HBV agents.

Compositions, Formation Mechanism, and Neuroprotective Effect of Compound Precipitation from the Traditional Chinese Prescription Huang-Lian-Jie-Du-Tang.

Compounds in the form of precipitation (CFP) are universally formed during the decocting of Chinese prescriptions, such as Huang-Lian-Jie-Du-Tang (HLJDT). The formation rate of HLJDT CFP even reached 2.63% ± 0.20%. The identification by liquid chromatography mass spectrometry (LC-MS(n)) proved that the main chemical substances of HLJDT CFP are baicalin and berberine, which is coincident with the theory that the CFP might derive from interaction between acidic and basic compounds. To investigate the formation mechanism of HLJDT CFP, baicalin and berberine were selected to synthesize a simulated precipitation and then the baicalin-berberine complex was obtained. Results indicated that the melting point of the complex interposed between baicalin and berberine, and the UV absorption, was different from the mother material. In addition, ¹H-NMR integral and high-resolution mass spectroscopy (HR-MS) can validate that the binding ratio was 1:1. Compared with baicalin, the chemical shifts of H and C on glucuronide had undergone significant changes by ¹H-, (13)C-NMR, which proved that electron transfer occurred between the carboxylic proton and the lone pair of electrons on the N atom. Both HLJDT CFP and the baicalin-berberine complex showed protective effects against cobalt chloride-induced neurotoxicity in differentiated PC12 cells. It is a novel idea, studying the material foundation of CFP in Chinese prescriptions.